New therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV

ABSTRACT

Described are compounds of formula I  
                 
 
     wherein at least one of the bonds in the five-membered ring is a double bond; B is any alpha or beta amino acid connected to the ring with an amide or peptide bond; or a salt thereof with a pharmaceutically acceptable acid or base. Pharmaceutical compositions containing these compounds are also described. These compounds are useful for treating type II diabetes.

FIELD OF INVENTION

[0001] The present invention relates to new therapeutically active andselective inhibitors of the enzyme DPP-IV, pharmaceutical compositionscomprising the compounds and the use of such compounds, and themanufacture of medicaments for treating diseases that are associatedwith proteins which are subject to inactivation by DPP-IV, such as typeII diabetes and obesity.

BACKGROUND OF THE INVENTION

[0002] Dipeptidyl peptidase-IV (DPP-IV), a serine protease belonging tothe group of post-proline/alanine cleaving amino-dipeptidases,specifically removes the two N-terminal amino acids from proteins havingproline or alanine in position 2.

[0003] Although the physiological role of DPP-IV has not been completelyestablished, it is believed to play an important role in neuropeptidemetabolism, T-cell activation, gastric ulceration, functional dyspepsia,obesity, appetite regulation, impaired fasting glucose (IFG) anddiabetes.

[0004] DPP-IV has been implicated in the control of glucose metabolismbecause its substrates include the insulinotropic hormones glucagon likepeptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIPare active only in their intact forms; removal of their two N-terminalamino acids inactivates them.

[0005] In vivo administration of synthetic inhibitors of DPP-IV preventsN-terminal degradation of GLP-1 and GIP, resulting in higher plasmaconcentrations of these hormones, increased insulin secretion and,therefore, improved glucose tolerance. Therefore, such inhibitors havebeen proposed for the treatment of patients with type II diabetes, adisease characterized by decreased glucose tolerance.

[0006] Unfortunately, the post-proline/alanine cleavingamino-dipeptidases are also implicated in the regulation of the immunesystem and inhibitors of these enzymes reportedly suppress immuneresponses. Thus, there is a risk that long-term treatment of type IIdiabetes with inhibitors of these enzymes may, as a side effect, lead toimmuno-suppression.

[0007] However, with the recent discoveries of otherpost-proline/alanine cleaving amino-dipeptidases that share the samesubstrate and inhibitor specificity as DPP-IV, including DPP-IVb,Attractin, X and QPP, it has become clear that such inhibitors mayinhibit multiple members of this group of enzymes. The precisephysiological role of each of these post-proline/alanine cleavingenzymes is not well defined. Consequently, it is not clear what thephysiological effect would be of inhibiting each of them separately, asubset, or all of them at the same time.

[0008] Diabetic dyslipidemia is characterized by multiple lipoproteindefects, including moderately high serum levels of cholesterol andtriglycerides, small LDL particles, and low levels of HDL cholesterol.The results of recent clinical trials reveal beneficial effects ofcholesterol-lowering therapy in diabetic and nondiabetic patients, thussupporting increased emphasis on treatment of diabetic dyslipidemia.This need for intensive treatment of diabetic dyslipidemia was advocatedby the National Cholesterol Education Program's Adult Treatment PanelII.

[0009] Obesity is a well-known risk factor for the development of manyvery common diseases such as atherosclerosis, hypertension and diabetes.The incidence of obese people and thereby also these diseases isincreasing throughout the entire industrialized world. Except forexercise, diet and food restriction no convincing pharmacologicaltreatment for reducing body weight effectively and acceptably currentlyexist. However, due to its indirect but important effect as a riskfactor in mortal and common diseases it will be important to findtreatment for obesity or appetite regulation. Even mild obesityincreases the risk for premature death, diabetes, hypertension,atherosclerosis, gallbladder disease and certain types of cancer. In theindustrialized western world the prevalence of obesity has increasedsignificantly in the past few decades. Because of the high prevalence ofobesity and its health consequences, its prevention and treatment shouldbe a high public health priority.

[0010] At present a variety of techniques are available to effectinitial weight loss. Unfortunately, initial weight loss is not anoptimal therapeutic goal. Rather, the problem is that most obesepatients eventually regain their weight. An effective means to establishand/or sustain weight loss is the major challenge in the treatment ofobesity today.

[0011] Thus there remains today a need in the art for compounds that areuseful for inhibiting DPP-IV without suppressing the immune system.

[0012] Several compounds have been shown to inhibit DPP-IV, but all ofthese have limitations in relation to the potency, stability,selectivity, toxicity, and/or pharmacodynamic properties.

[0013] Such compounds have e.g. been disclosed in WO 98/19998, WO00/34241, U.S. Pat. No. 6,124,305 (Novartis AG) and WO 99/38501(Trustees of Tufts University).

[0014] Thus, there is a need for novel DPP-IV inhibitors that aresuperior with respect to one or more of the above listed properties, andwhich will be useful for the treatment of conditions, which may beregulated or normalized by inhibition of DPP-IV.

SUMMARY OF THE INVENTION

[0015] The present invention provides novel 2-substituted unsaturatedheterocyclic compounds, wherein a nitrogen atom in the heterocyclic ringis attached via an amide bond or a peptide bond to an amino acid or anamino acid derivative. These compounds are potent and selectiveinhibitors of DPP-IV, and are effective in treating conditions that maybe regulated or normalized via inhibition of DPP-IV. The invention alsoconcerns pharmaceutical compositions comprising the compounds, a methodof inhibiting DPP-IV comprising administering to a patient in need ofsuch treatment a therapeutically effective amount thereof, the compoundsfor use as a pharmaceutical, and their use in a process for thepreparation of a medicament for treating a condition which may beregulated or normalized via inhibition of DPP-IV.

DEFINITIONS

[0016] The term “DPP-IV” as used herein is intended to mean Dipeptidylpeptidase IV (EC 3.4.14.5; DPP-IV), also known as CD26. DPP-IV cleaves adipeptide from the N terminus of a polypeptide chain containing aproline or alanine residue in the penultimate position.

[0017] The term “treatment” is defined as the management and care of apatient for the purpose of combating the disease, condition, or disorderand includes the administration of a compound of the present inventionto prevent the onset of the symptoms or complications, or alleviatingthe symptoms or complications, or eliminating the disease, condition, ordisorder.

[0018] The term “beta cell degeneration” is intended to mean loss ofbeta cell function, beta cell dysfunction, and death of beta cells, suchas necrosis or apoptosis of beta cells.

[0019] The term “C₁-C₁₀ alkyl” as used herein, alone or in combination,refers to a straight or branched, saturated hydrocarbon chain havingfrom 1-10 carbon atoms such as but not limited to e.g. methyl, ethyl,n-propyl, isopropyl, n-butyl, sec. Butyl, isobutyl, tert. Butyl,n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl,neopentyl, 2,2-dimethylpropyl and the like.

[0020] The term “C₂-C₁₀-alkenyl” used herein, alone or in combination,refers to a straight or branched, unsaturated hydrocarbon chain havingfrom 2-10 carbon atoms and at least one double bond such as, but notlimited to, vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyland n-hexenyl and the like.

[0021] The term “C₂-C₁₀ alkynyl” as used herein, alone or incombination, refers to an unsaturated hydrocarbon chain having from 2-10carbon atoms and at least one triple bond such as but not limited to—C≡CH, —C≡CCH₃, —CH₂C≡CH, —CH₂—CH₂—C≡CH, —CH(CH₃)C≡CH and the like.

[0022] The term “C₁₋₁₀-alkoxy” as used herein, alone or in combinationis intended to include those C₁₋₁₀-alkyl groups of the designated lengthin either a linear or branched or cyclic configuration linked through anether oxygen having its free valence bond from the ether oxygen.Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy,pentoxy and hexoxy. Examples of branched alkoxy are isoprpoxy,sec-butoxy, tert-butoxy, isopentoxy and isohexoxy. Examples of cyclicalkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy andcyclohexyloxy.

[0023] The term “C₃-C₁₀ cycloalkyl” as used herein refers to a radicalof one or more saturated cyclic hydrocarbon having from 3-10 carbonatoms such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, adamantyl and the like.

[0024] The term “C₃-C₁₀ cycloalkane” as used herein refers to asaturated cyclic hydrocarbon having from 3-10 carbon atoms such as, butnot limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane,adamantane and the like.

[0025] The term “C₅-C₁₀ cycloalkenyl” as used herein refers to a radicalof one or more cyclic hydrocarbon having at least one double bond havingfrom 5-10 carbon atoms such as, but not limited to, cyclopentenyl,cyclohexenyl and the like.

[0026] The term “aryl” as used herein includes carbocyclic aromatic ringsystems. Aryl is also intended to include the partially hydrogenatedderivatives of the carbocyclic systems.

[0027] The term “heteroaryl” as used herein includes heterocyclicunsaturated ring systems containing one or more heteroatoms selectedfrom nitrogen, oxygen and sulphur such as furyl, thienyl, pyrrolyl.Heteroaryl is also intended to include the partially hydrogenatedderivatives of the heterocyclic systems enumerated below.

[0028] The terms “aryl” and “heteroaryl” as used herein refers to anaryl which can be optionally substituted or a heteroaryl which can beoptionally substituted and includes phenyl, biphenyl, indenyl, naphthyl(1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl,N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl,3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl,3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl,xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl(2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[bjfuranyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1 -benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl).

DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention provides compounds of formula I

[0030] wherein

[0031] at least one of the bonds in the five-membered ring is a doublebond;

[0032] B is any alpha or beta amino acid connected to the ring with anamide or peptide bond;

[0033] or a salt thereof with a pharmaceutically acceptable acid orbase.

[0034] In a preferred embodiment the invention provides compounds offormula II

[0035] wherein

[0036] at least one of the bonds in the five-membered ring is a doublebond;

[0037] R² is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently;

[0038] R³ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀ cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently and/or fused to a C₃-C₁₀ cycloalkane; or heteroaryloptionally substituted with one or more R⁵ independently and/or fused toa C₃-C₁₀ cycloalkane;

[0039] R² may be connected to R³ by a saturated or unsaturated bridgecontaining 1-3 carbon atoms, nitrogen atoms, oxygen atoms or sulphuratoms independently, or a valence bond, thus forming a ring, said ringmay be fused to an aryl or heteroaryl, optionally substituted by one ormore R⁵ independently;

[0040] R⁴ is cycloalkyl, aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; amino optionally substituted with one or more R⁶independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶, —CONH—R⁶; —CON(R⁶)₂;—O—R⁶; —S—R⁶; carboxy; acetamido; cyano; nitro; halogen; hydroxy;trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;

[0041] R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxyimino,cyano; carboxy; acetamido; hydroxy; sulfamoyl, carbamoyl;

[0042] R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀-alkynyl,C₃-C₁₀-cycloalkyl, C₅-C₁₀ cycloalkenyl where any one of said alkyl,alkenyl, alkynyl, cycloalkyl, or cykloalkenyl may optionally besubstituted with aryl optionally substituted with one or more R⁵independently or heteroaryl optionally substituted with one or more R⁵independently; benzyl, phenethyl; aryl optionally substituted with oneor more R⁵ independently; or heteroaryl optionally substituted with oneor more R⁵ independently

[0043] with the proviso that R² and R³ cannot both be H;

[0044] or a salt thereof with a pharmaceutically acceptable acid orbase.

[0045] In a preferred embodiment the invention provides compounds offormula III

[0046] wherein

[0047] R² is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently;

[0048] R³ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀ cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently and/or fused to a C₃-C₁₀ cycloalkane; or heteroaryloptionally substituted with one or more R⁵ independently and/or fused toa C₃-C₁₀ cycloalkane;

[0049] R² may be connected to R³ by a saturated or unsaturated bridgecontaining 1-3 carbon atoms, nitrogen atoms, oxygen atoms or sulphuratoms independently, or a valence bond, thus forming a ring, said ringmay be fused to an aryl or heteroaryl, optionally substituted by one ormore R⁵ independently;

[0050] R⁴ is cycloalkyl, aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; amino optionally substituted with one or more R⁶independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶, —CONH—R⁶; —CON(R⁶)₂;—O—R⁶; —S—R⁶; carboxy; acetamido; cyano; nitro; halogen; hydroxy;trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;

[0051] R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxyimino,cyano; carboxy; acetamido; hydroxy; sulfamoyl, carbamoyl;

[0052] R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀-alkynyl,C₃-C₁₀-cycloalkyl, C₅-C₁₀ cycloalkenyl where any one of said alkyl,alkenyl, alkynyl, cycloalkyl, or cykloalkenyl may optionally besubstituted with aryl optionally substituted with one or more R⁵independently or heteroaryl optionally substituted with one or more R⁵independently; benzyl, phenethyl; aryl optionally substituted with oneor more R⁵ independently; or heteroaryl optionally substituted with oneor more R⁵ independently

[0053] with the proviso that R² and R³ cannot both be H;

[0054] or a salt thereof with a pharmaceutically acceptable acid orbase.

[0055] In another preferred embodiment, the invention provides compoundsof formula IV

[0056] wherein

[0057] at least one of the bonds in the five-membered ring is a doublebond;

[0058] R² is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently;

[0059] R³ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀ cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently and/or fused to a C₃-C₁₀ cycloalkane; or heteroaryloptionally substituted with one or more R⁵ independently and/or fused toa C₃-C₁₀ cycloalkane;

[0060] R² may be connected to R³ or R⁷ by a saturated or unsaturatedbridge containing 1-3 carbon atoms, nitrogen atoms, oxygen atoms orsulphur atoms independently, or a valence bond, thus forming a ring,said ring may be fused to an aryl or heteroaryl, optionally substitutedby one or more R⁵ independently;

[0061] R⁴ is cycloalkyl, aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; amino optionally substituted with one or more R⁶independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶, —CONH—R⁶; —CON(R⁶)₂;—O—R⁶; —S—R⁶; carboxy; acetamido; cyano; nitro; halogen; hydroxy;trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;

[0062] R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxyimino,cyano; carboxy; acetamido; hydroxy; sulfamoyl, carbamoyl;

[0063] R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀-alkynyl,C₃-C₁₀-cycloalkyl, C₅-C₁₀ cycloalkenyl where any one of said alkyl,alkenyl, alkynyl, cycloalkyl, or cykloalkenyl may optionally besubstituted with aryl optionally substituted with one or more R⁵independently or heteroaryl optionally substituted with one or more R⁵independently; benzyl, phenethyl; aryl optionally substituted with oneor more R⁵ independently; or heteroaryl optionally substituted with oneor more R⁵ independently;

[0064] R⁷ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently, halogen, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, C₁-C₁₀alkylamino, C₁-C₁₀ dialkylamino, hydroxymethyl, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano; carboxy;acetamido; hydroxy; sulfamoyl, carbamoyl;

[0065] with the proviso that the groups R², R³, and R⁷ cannot all be H.

[0066] or a salt thereof with a pharmaceutically acceptable acid orbase.

[0067] In another preferred embodiment, the invention provides compoundsof formula V

[0068] wherein

[0069] R² is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently;

[0070] R³ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀ cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently and/or fused to a C₃-C₁₀ cycloalkane; or heteroaryloptionally substituted with one or more R⁵ independently and/or fused toa C₃-C₁₀ cycloalkane;

[0071] R² may be connected to R³ or R⁷ by a saturated or unsaturatedbridge containing 1-3 carbon atoms, nitrogen atoms, oxygen atoms orsulphur atoms independently, or a valence bond, thus forming a ring,said ring may be fused to an aryl or heteroaryl, optionally substitutedby one or more R⁵ independently;

[0072] R⁴ is cycloalkyl, aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; amino optionally substituted with one or more R⁶independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶, —CONH—R⁶; —CON(R⁶)₂;—O—R⁶; —S—R⁶; carboxy; acetamido; cyano; nitro; halogen; hydroxy;trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;

[0073] R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino,C₁-C₁₀ dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, N-hydroxyimino,cyano; carboxy; acetamido; hydroxy; sulfamoyl, carbamoyl;

[0074] R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀-alkynyl,C₃-C₁₀-cycloalkyl, C₅-C₁₀ cycloalkenyl where any one of said alkyl,alkenyl, alkynyl, cycloalkyl, or cykloalkenyl may optionally besubstituted with aryl optionally substituted with one or more R⁵independently or heteroaryl optionally substituted with one or more R⁵independently; benzyl, phenethyl; aryl optionally substituted with oneor more R⁵ independently; or heteroaryl optionally substituted with oneor more R⁵ independently;

[0075] R⁷ is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently, halogen, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, C₁-C₁₀alkylamino, C₁-C₁₀ dialkylamino, hydroxymethyl, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano; carboxy;acetamido; hydroxy; sulfamoyl, carbamoyl;

[0076] with the proviso that the groups R², R³, and R⁷ cannot all be H.

[0077] or a salt thereof with a pharmaceutically acceptable acid orbase.

[0078] A further preferred embodiment is represented by the compounds ofthe invention wherein:

[0079] R² is H; C₁-C₁₀ alkyl optionally substituted with R⁴; C₂-C₁₀alkenyl optionally substituted with R⁴; C₂-C₁₀-alkynyl optionallysubstituted with R⁴; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently;

[0080] R² may be connected to R³ or R⁷ by a saturated or unsaturatedbridge containing 1-3 carbon atoms, nitrogen atoms, oxygen atoms, orsulphur atoms independently, or a valence bond, thus forming a ring,said ring may be fused to an aryl or heteroaryl, optionally substitutedby one or more R⁵ independently;

[0081] Another preferred embodiment is represented by the compounds ofthe invention wherein R² is H or C₁-C₁₀ alkyl optionally substitutedwith R⁴.

[0082] Another preferred embodiment is represented by the compounds ofthe invention wherein R² is H.

[0083] Another preferred embodiment is represented by the compounds ofthe invention wherein:

[0084] R³ is H; C₁-C₁₀ alkyl optionally substituted with R⁴; C₂-C₁₀alkenyl optionally substituted with R⁴; C₂-C₁₀-alkynyl optionallysubstituted with R⁴; C₃-C₁₀ cycloalkyl optionally substituted with R⁴;aryl optionally substituted with one or more R⁵ independently and/orfused to a C₃-C₁₀ cycloalkane; or heteroaryl optionally substituted withone or more R⁵ independently and/or fused to a C₃-C₁₀ cycloalkane;

[0085] Another preferred embodiment is represented by the compounds ofthe invention wherein:

[0086] R³ is H; C₁-C₁₀ alkyl optionally substituted with R⁴; or aryloptionally substituted with one or more R⁵ independently and/or fused toa C₃-C₁₀ cycloalkane.

[0087] Another preferred embodiment is represented by the compounds ofthe invention wherein R³ is C₁-C₁₀ alkyl optionally substituted with R⁴.

[0088] Another preferred embodiment is represented by the compounds ofthe invention wherein:

[0089] R⁴ is cycloalkyl; aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶; —O—R⁶; —S—R⁶;

[0090] Another preferred embodiment is represented by the compounds ofthe invention wherein:

[0091] R⁴ is aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; —CO—R⁶; —COO—R⁶; —O—R⁶; —S—R⁶;

[0092] Another preferred embodiment is represented by the compounds ofthe invention wherein R⁴ is aryl optionally substituted with one or moreR⁵ independently;

[0093] Another preferred embodiment is represented by the compounds ofthe invention wherein R⁴ is —COO—R⁶, —O—R⁶, or —S—R⁶;

[0094] Another preferred embodiment is represented by the compounds ofthe invention wherein R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy,C₁-C₁₀l alkylamino, C₁-C₁₀ dialkylamino, benzyl, or benzyloxy.

[0095] Another preferred embodiment is represented by the compounds ofthe invention wherein R⁵ is halogen, C₁-C₁₀ alkyl, or C₁-C₁₀ alkoxy.

[0096] Another preferred embodiment is represented by the compounds ofthe invention wherein R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl optionallysubstituted with R⁴; C₂-C₁₀-alkynyl optionally substituted with R⁴;benzyl, aryl optionally substituted with one or more R⁵ independently,or heteroaryl optionally substituted with one or more R⁵ independently.

[0097] Another preferred embodiment is represented by the compounds ofthe invention wherein R⁶ is C₁-C₁₀ alkyl, benzyl, or aryl optionallysubstituted with one or more R⁵ independently.

[0098] The most preferred compounds of formula I wherein B represents analpha-amino acid are the following:

[0099] (S,S) 1-(2-Amino-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0100] (S,S) 1-(2-Amino-butyryl)- 2,5-dihydro-1H-pyrrole-2-carbonitrile

[0101] (S,S)1-(2-Amino-3-methyl-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0102] (S,S)1-(2-Amino-3,3-dimethyl-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0103] (S,S)1-(2-Amino-4-methyl-pent-4-enoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0104] (S,S)1-(2-Amino-3,3-diethyl-pentanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0105] (S,S)1-(2-Amino-2-cyclopentylacetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0106] (S,S)1-(2-Amino-2-cyclohexylacetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0107] (S,S)1-(2-Amino-2-cycloheptylacetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0108] (S,S)1-(2-Amino-2-bicyclo[2.2.2]oct-1-yl-acetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0109] (S,S)1-(2-Adamantan-1-yl-2-amino-acetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0110] (S,S)1-(2-Amino-2-phenylacetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0111] (S,S) 1-(2-Amino-2-(2,6dimethylphenyl)acetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0112] (S,S)1-(2-Amino-3,3-diphenyl-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0113] (S,S)1-(2-Amino-(3(R)-methylpentanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0114] (S,S)1-(2-Amino-(4-methylpentanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0115] (S,S)1-(2,6-Diamino-hexanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0116] (S,S)1-(2-Amino-6-dibenzylamino-hexanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0117] (S,S)1-(2-Amino-6-benzylamino-hexanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0118] (S,S)[5-Amino-6-(2-cyano-2,5-dihydro-pyrrol-1-yl)-6-oxo-hexyl]-carbamicacid-tert-butyl ester

[0119] (S,S)(5-Amino-6-(2-cyano-2,5-dihydro-pyrrol-1-yl)-6-oxo-hexyl]-carbamic acid9-H-fluoren-9-ylmethyl ester

[0120] (S,S) 4-Amino-5-(2-cyano-2,5-dihydro-pyrrol-1-yl)-5-oxo-pentanoicacid amide

[0121] (S,S) 4-Amino-5-(2-cyano-2,5-dihydro-pyrrol-1-yl)-5-oxo-pentanoicacid benzylamide

[0122] (S,S) 4-Amino-5-(2-cyano-2,5-dihydro-pyrrol-1-yl)-5-oxo-pentanoicacid benzyl ester

[0123] (S,S) 4-Amino-5-(2-cyano-2,5-dihydro-pyrrol-1-yl)-5-oxo-pentanoicacid-tert-butyl ester

[0124] (S,S)1-(2-Amino-3-benzyloxy-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0125] (S,S)1-(2-Amino-(4-methylsulfanyl-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0126] (S,S)1-(2-Amino-(3-phenylpropionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0127] (S,S)1-(Pyrrolidine-2-carbonyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0128] (S,S)6-{2-[2-(2-Cyano-2,5-dihydro-pyrrol-1-yl)-2-oxo-ethylamino]-ethylamino}-nicotino-nitrile

[0129] (S,S)1-{2-[2-(5-Chloro-pyridin-2-ylamino)-ethylamino]-acetyl}-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0130] (S,S)1-{2-[2-(5-Trifluoromethyl-pyridin-2-ylamino)-ethylamino]-acetyl}-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0131] (S,S)1-[2-(1-Hydroxymethyl-cyclopentylamino)-acetyl]-2,5-dihydro-1H-pyrrole-2-carbonitrile

[0132] (S,S)1-{2-[2-(5-Nitro-pyridin-2-ylamino)-ethylamino]-acetyl}-2,5-dihydro-1H-pyrrole-2-carbonitrile.and

[0133] (S,S)1-[2-(3-Isopropoxy-propylamino)-acetyl]-2,5-dihydro-1H-pyrrole-2-carbonitrile.

[0134] The most preferred compounds of formula I wherein B represents abeta-amino acid are the following:

[0135]1-(Piperidine-3-carbonyl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0136]1-(cis(2-Amino-cyclopenanecarbonyl))-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0137]1-(3-R-Amino-5-phenyl-pentanoyl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0138]1-(3-S-Amino-5-phenyl-pentanoyl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0139]1-(3-S-Amino-4-phenyl-butyryl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0140]1-(3-R-Amino-3-phenyl-propionyl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0141]1-(Morpholine-2-carbonyl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0142]1-(3-R-Amino-6-phenyl-hex-5-enoyl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0143]1-(3-R-Amino-4-benzo[b]thiophen-2-yl-butyryl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0144]1-(3-R-amino-4-pyridin-3-yl-butyryl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0145]1-[3-S-Amino-4-(4-benzyloxy-phenyl)-butyryl]-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0146]1-[2-S-Pyrolidin-2-yl-acetyl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0147]1-[4-(2-Chloro-phenyl)-pyrrolidine-3-carbonyl]-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0148]1-(4-R-Phenyl-pyrrolidine-3-S-carbonyl)-2,5-dihydro-1-H-pyrrole-2-S-carbonitrile

[0149] or a salt thereof with a pharmaceutically acceptable acid orbase.

[0150] The invention also relates to methods for preparing theabove-mentioned compounds. These methods comprise (1) and (2) describedbelow:

[0151] (1) Reacting an alpha amino acid or a beta-amino acid, suitablyamino-protected with a standard protecting group such as Boc—, Fmoc—,CBz— or the like, with a 2-carbamoyl substituted unsaturatedheterocyclic compound of formula VI,

[0152] under standard peptide coupling conditions to give an amideproduct; dehydrating the carbamoyl functionality of this material usingstandard dehydrating agents such as phosphorous oxycloride in pyridineor DMF, or trifluoroacetic acid anhydride, or thebromine/triphenylphospine adduct to give the nitrile, and to deprotectthe amino group using standard chemical transformations to give thecompounds of the invention.

[0153] (2) Reacting a 2-carbamoyl substituted unsaturated heterocycliccompound of formula VI,

[0154] with an alpha-halogenated carboxylic acid chloride, bromide, oranhydride to give a compound of formula VII,

[0155] dehydrating the carbamoyl functionality of this material usingstandard dehydrating agents such as phosphorous oxycloride in pyridineor DMF, or trifluoroacetic acid anhydride, or thebromine/triphenylphospine adduct to give the nitrile, and reacting thenitrile compound with an appropriately substituted amine to give thecompounds of the invention.

[0156] The compounds of the present invention may be prepared in theform of pharmaceutically acceptable salts, especially acid-additionsalts, including salts of organic acids and mineral acids. Examples ofsuch salts include salts of organic acids such as formic acid, fumaricacid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvicacid, oxalic acid, succinic acid, malic acid, tartaric acid, citricacid, benzoic acid, salicylic acid and the like. Suitable inorganicacid-addition salts include salts of hydrochloric, hydrobromic,sulphuric and phosphoric acids and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are known to the skilledartisan.

[0157] Also intended as pharmaceutically acceptable acid addition saltsare the hydrates which the present compounds are able to form.

[0158] The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent.

[0159] The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

[0160] It is to be understood that the invention extends to all of thestereo isomeric forms of the claimed compounds, as well as theracemates.

[0161] A further aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treating a conditionthat may be regulated or normalized via inhibition of DPP-IV.

[0162] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of metabolicdisorders.

[0163] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for blood glucoselowering.

[0164] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of type IIdiabetes.

[0165] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofimpaired glucose tolerance (IGT).

[0166] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofimpaired fasting glucose (IFG).

[0167] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for prevention ofhyperglycemia.

[0168] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for delaying theprogression of impaired glucose tolerance (IGT) to type II diabetes.

[0169] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for delaying theprogression of non-insulin requiring type II diabetes to insulinrequiring type II diabetes.

[0170] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for increasing the numberand/or the size of beta cells in a mammalian subject.

[0171] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of beta celldegeneration, in particular apoptosis of beta cells.

[0172] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofdisorders of food intake.

[0173] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofobesity.

[0174] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for appetite regulation orinduction of satiety.

[0175] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofdyslipidemia.

[0176] Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment offunctional dyspepsia, in particular irritable bowel syndrome.

[0177] A further aspect of the invention is a method for treating theconditions mentioned above by administering to a subject in need thereofan effective amount of a compound of the invention.

Combination Treatments

[0178] The invention furthermore relates to the use of a compoundaccording to the present invention for the preparation of a medicamentfor use in the treatment of diabetes in a regimen that additionallycomprises treatment with another antidiabetic agent.

[0179] In one embodiment of this invention, the antidiabetic agent isinsulin or GLP-1 or any analogue or derivative thereof.

[0180] In another embodiment the antidiabetic agent is a non-peptidylhypoglycemic agent, preferably an oral hypoglycemic agent.

[0181] Oral hypoglycemic agents are preferably selected from the groupconsisting of sulfonylureas, non-sulphonylurea insulin secretagogues,biguanides, thiazolidinediones, alpha glucosidase inhibitors, glucagonantagonists, GLP-1 agonists, potassium channel openers, insulinsensitizers, hepatic enzyme inhibitors, glucose uptake modulators,compounds modifying the lipid metabolism, compounds lowering foodintake, and agents acting on the ATP-dependent potassium channel of theβ-cells.

[0182] Among the sulfonylureas, tolbutamide, glibenclamide, glipizideand gliclazide are preferred.

[0183] Among the non-sulphonylurea insulin secretagogues, repaglinideand nateglinide are preferred.

[0184] Among the biguanides, metformin is preferred.

[0185] Among the thiazolidinediones, troglitazone, rosiglitazone andciglitazone are preferred.

[0186] Among the glucosidase inhibitors, acarbose is preferred.

[0187] Among the agents acting on the ATP-dependent potassium channel ofthe β-cells the following are preferred: glibenclamide, glipizide,gliclazide, repaglinide.

Pharmaceutical Compositions

[0188] In another aspect, the present invention includes within itsscope pharmaceutical compositions comprising, as an active ingredient,at least one compound of the invention which inhibits the enzymaticactivity of DPP-IV or a pharmaceutically acceptable salt or prodrug orhydrate thereof together with a pharmaceutically acceptable carrier ordiluent.

[0189] Pharmaceutical compositions containing a compound of theinvention of the present invention may be prepared by conventionaltechniques, e.g. as described in Remington: The Science and Practise ofPharmacy, 19th Ed., 1995. The compositions may appear in conventionalforms, for example capsules, tablets, aerosols, solutions, suspensionsor topical applications.

[0190] Typical compositions include a compound of the invention whichinhibits the enzymatic activity of DPP-IV or a pharmaceuticallyacceptable basic addition salt or prodrug or hydrate thereof, associatedwith a pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material that acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin,magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate,talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethersof cellulose, silicic acid, fatty acids, fatty acid amines, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.Similarly, the carrier or diluent may include any sustained releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate, alone or mixed with a wax. The formulations may also includewetting agents, emulsifying and suspending agents, preserving agents,sweetening agents or flavoring agents. The formulations of the inventionmay be formulated so as to provide quick, sustained, or delayed releaseof the active ingredient after administration to the patient byemploying procedures well known in the art.

[0191] The pharmaceutical compositions can be sterilized and mixed, ifdesired, with auxiliary agents, emulsifiers, salt for influencingosmotic pressure, buffers and/or coloring substances and the like, whichdo not deleteriously react with the active compounds.

[0192] The route of administration may be any route, which effectivelytransports the active compound of the invention which inhibits theenzymatic activity of DPP-IV to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, buccal, subdermal, intradermal,transdermal or parenteral, e.g., rectal, depot, subcutaneous,intravenous, intraurethral, intramuscular, intranasal, ophthalmicsolution or an ointment, the oral route being preferred.

[0193] If a solid carrier is used for oral administration, thepreparation may be tabletted, placed in a hard gelatin capsule in powderor pellet form or it can be in the form of a troche or lozenge. If aliquid carrier is used, the preparation may be in the form of a syrup,emulsion, soft gelatin capsule or sterile injectable liquid such as anaqueous or non-aqueous liquid suspension or solution.

[0194] For nasal administration, the preparation may contain a compoundof the invention which inhibits the enzymatic activity of DPP-IV,dissolved or suspended in a liquid carrier, in particular an aqueouscarrier, for aerosol application. The carrier may contain additives suchas solubilizing agents, e.g., propylene glycol, surfactants, absorptionenhancers such as lecithin (phosphatidylcholine) or cyclodextrin, orpreservatives such as parabenes.

[0195] For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

[0196] Tablets, dragees, or capsules having talc and/or a carbohydratecarrier or binder or the like are particularly suitable for oralapplication. Preferable carriers for tablets, dragees, or capsulesinclude lactose, corn starch, and/or potato starch. A syrup or elixircan be used in cases where a sweetened vehicle can be employed.

[0197] A typical tablet that may be prepared by conventional tablettingtechniques may contain: Core: Active compound (as free compound or saltthereof) 250 mg Colloidal silicon dioxide (Aerosil) ® 1.5 mg Cellulose,microcryst. (Avicel) ® 70 mg Modified cellulose gum (Ac-Di-Sol) ® 7.5 mgMagnesium stearate Ad. Coating: HPMC approx. 9 mg *Mywacett 9-40 Tapprox. 0.9 mg

[0198] The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of the various diseases as mentioned above,e.g., type II diabetes, IGT, IFG, obesity, appetite regulation or as ablood glucose lowering agent, and especially type II diabetes. Suchmammals include also animals, both domestic animals, e.g. householdpets, and non-domestic animals such as wildlife.

[0199] The compounds of the invention are effective over a wide dosagerange. For example, in the treatment of adult humans, dosages from about0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, perday may be used. A most preferable dosage is about 0.5 mg to about 250mg per day. In choosing a regimen for patients it may frequently benecessary to begin with a higher dosage and when the condition is undercontrol to reduce the dosage. The exact dosage will depend upon the modeof administration, on the therapy desired, form in which administered,the subject to be treated and the body weight of the subject to betreated, and the preference and experience of the physician orveterinarian in charge.

[0200] Generally, the compounds of the present invention are dispensedin unit dosage form comprising from about 0.05 to about 1000 mg ofactive ingredient together with a pharmaceutically acceptable carrierper unit dosage.

[0201] Usually, dosage forms suitable for oral, nasal, pulmonal ortransdermal administration comprise from about 0.05 mg to about 1000 mg,preferably from about 0.5 mg to about 250 mg of the compounds admixedwith a pharmaceutically acceptable carrier or diluent.

[0202] The invention also encompasses prodrugs of a compound of theinvention which on administration undergo chemical conversion bymetabolic processes before becoming active pharmacological substances.In general, such prodrugs will be functional derivatives of a compoundaf the invention which are readily convertible in vivo into a compoundof the invention. Conventional procedures for the selection andpreparation of suitable prodrug derivatives are described, for example,in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0203] The invention also encompasses active metabolites of a compoundof the invention.

[0204] Methods for measuring the activity of compounds which inhibit theenzymatic activity of CD26/DPP-IV

[0205] Summary.

[0206] Chemical compounds are tested for their ability to inhibit theenzyme activity of purified CD26/DPP-IV. Briefly, the activity ofCD26/DPP-IV is measured in vitro by its ability to cleave the syntheticsubstrate Gly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNAby DPP-IV liberates the product p-nitroanilide (pNA), whose rate ofappearance is directly proportional to the enzyme activity. Inhibitionof the enzyme activity by specific enzyme inhibitors slows down thegeneration of pNA. Stronger interaction between an inhibitor and theenzyme results in a slower rate of generation of pNA. Thus, the degreeof inhibition of the rate of accumulation of pNA is a direct measure ofthe strength of enzyme inhibition. The accumulation of pNA is measuredspectrophotometrically. The inhibition constant, Ki, for each compoundis determined by incubating fixed amounts of enzyme with severaldifferent concentrations of inhibitor and substrate.

[0207] Materials:

[0208] The following reagents and cells are commercially available:

[0209] Porcine CD26/DPP-IV (Sigma D-7052), Gly-Pro-pNA (Sigma G0513).

[0210] Assay buffer: 50 mM Tris pH7.4, 150 mM NaCl, 0,1% Triton X-100.

[0211] Gly-Pro-pNA cleavage-assay for CD26:

[0212] The activity of purified CD26/DPP-IV is assayed in reactionscontaining:

[0213] 70 ul assay buffer

[0214] 10 ul inhibitor or buffer

[0215] 10 ul substrate (Gly-Pro-pNA from a 0.1M stock solution in water)or buffer

[0216] 10 ul enzyme or buffer

[0217] Reactions containing identical amounts of enzyme, but varyingconcentrations of inhibitor and substrate, or buffer as control, are setup in parallel in individual wells of a 96-well ELISA plate. The plateis incubated at 25° C. and absorbance is read at 405 nm after 60 minincubation. The inhibitor constants are calculated by nonlinearregression hyperbolic fit and the result is expressed as inhibitionconstant (Ki) in nM.

[0218] Diabetes model

[0219] The Zucker Diabetic Fatty (ZDF) rat model can be used toinvestigate the effects of the compounds of the invention on both thetreatment and prevention of diabetes as rats of this sub-strain areinitially pre-diabetic although develop severe type 2 diabetescharacterized by increased HbA1 c levels over a period of 6 weeks. Thesame strain can be used to predict the clinical efficacy of otheranti-diabetic drug types. For example, the model predicts the potencyand limited clinical efficacy of thiazolidinedione insulin sensitizercompounds.

EXAMPLES

[0220] A further detailed description of the invention is given withreference to the following examples.

Example 1 (S,S) 1-(2-Amino-3,3-dimethyl-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(1)

[0221] (S)-2-Amino-N-tert-butyloxycarbonyl-3,3-dimethylbutyric acid (308mg, 1.33 mmol) was dissolved in 3 ml of dichloromethane and1-hydroxy-7-azabenzotriazole (HOAT) (180 mg, 1.33 mmol) and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, hydrochloride (EDAC)(258 mg, 1.35 mmol) was added. The mixture was stirred at roomtemperature for 30 minutes, and then (S)2,5-dihydro-1H-pyrrole-2-carboxylic acid amide, (150 mg, 1.33 mmol) anddiisopropylethylamine (0.46 ml, 2.68 mmol) were added. The reactionmixture was stirred at room temperature for 20 hours. The solvent wasevaporated and the crude product was purified by preparative HPLC, usingacetonitrile/water as the eluent. Fractions containing the product werecollected and the solvents were evaporated, to afford 200 mg of (S,S)[1-(2-Carbamoyl-2,5-dihydro-pyrrole-1-carbonyl)-2,2-dimethyl-propyl]-carbamicacid tert-butyl ester (2). Oil, 47% yield. ¹H-NMR (CDCl₃, 200 MHz) δ:1.03 (s, 9H); 1.42 (s, 9H); 4.29 (d, 1H); 4.36-4.50 (m, 1H); 4.62-4.73(m,1H); 5.25-5.33 (m, 2H); 5.85-6.00 (m, 3H); 6.88 (br. s, 1H).

[0222] (175 mg, 0.54 mmol) of (2) was dissolved in 4 ml of pyridine andthe mixture was cooled to 0° C. Phosphorus oxychloride (0.2 ml, 2.15mmol) was added dropwise and after 10 minutes of stirring the reactionmixture was poured into 20 ml of ice water and the organic material wasextracted into 5×10 ml of ethyl acetate. The combined organic extractwas washed with 2×20 ml of water, 1×20 ml of brine and dried overmagnesium sulphate. The solvent was evaporated to afford 140 mg of (S,S)[1-(2-Cyano-2,5-dihydro-pyrrole-1-carbonyl)-2,2-dimethyl-propyl]-carbamicacid tert-butyl ester (3). Oil, 85% yield. ¹H-NMR (CDCl₃, 200 MHz) δ:1.05 (s, 9H); 1.42 (s, 9H); 4.22 (d, 1H); 4.39-4.53 (m, 1H); 4.65-4.77(m, 1H); 5.30 (d, 1H); 5.41-5.48 (m, 1H); 5.83-5.90 (m, 1H); 6.09-6.15(m, 1H).

[0223] (140 mg, 0.46 mmol) of (3) was dissolved in 0.5 ml ofdichloromethane and the mixture was cooled to 0° C. 0.5 ml oftrifluoroacetic acid was added and the reaction mixture was stirred at0° C. for 1 hour. The solvent was evaporated and the crude product waspurified by preparative HPLC, using acetonitrile/water as the eluent.Fractions containing the product were collected and the solvent wasevaporated, to afford 25 mg of the title compound (1) as thetrifluoroacetic acid salt. Oil, 17% yield. ¹H-NMR (MeOH, 200 MHz) δ:1.20 (s, 9H); 4.08 (s, 1H); 4.46-4.70 (m, 2H); 5.56-5.62 (m, 1H);5.95-6.02 (m, 1H); 6.22-6.29 (m, 1H). LC-MS, m/z: 208.4 (M+1)

[0224] The following compounds were prepared essentially by the routeoutlined in example 1; however, most compounds were also purified bypreparative HPLC after the dehydration step.

[0225] (S,S)1-(2-Amino-4-methyl-pent-4-enoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(2)

[0226] (29 mg) LC-MS (El), m/z: 206 (M+1). Prepared from (S)2-tert-Butoxycarbonylamino-4-methyl-pent-4-enoic acid.

[0227] (S,S)1-(Pyrrolidine-2-carbonyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile (3)

[0228] (30 mg) 1H-NMR (CDCl3, 200 MHz) δ: 6.13 (d, 1H); 5.90 (d, 1H);5.50 (s, 1H); 4.78 (s, 1H); 4.46 (m, 2H); 3.53 (s, 2H); 2.52 (s, 1H);2.18 (m, 3H); 1.4 (m, 1H). LC-MS (El), m/z: 192 (M+1). Prepared fromN-Boc-proline.

[0229] (S,S)1-(2-Amino-3-phenyl-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile (4)

[0230] (27 mg). 1H-NMR (CDCl3, 200 MHz) δ: 7.30 (m, 5H); 5.85 (dd, 1H);5.70 (dd, 1H); 5.38 (m, 1H); 3.33 (dd, 1H); 4.2 (dd, 1H); 3.33, (dd,IH); 3.15 (dd, 1H); 2.88 (dd, 1H). LC-MS (El), m/z: 242 (M+1). Preparedfrom N-Boc-Phenylalanine.

[0231] (S,S)1-(2-Amino-4-methyl-pentanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile (5)

[0232] (66 mg). 1H-NMR (CDCl3, 200 MHz) δ: 6.17 (dd, 1H); 5.90 (dd, 1H);5.50 (m, 1H); 4.63 (dd, 1H); 4.38-4.28 (dd, 1H); 4.28-4.15 (dd, 1H);1.92-1.54 (m, 3H); 1.00 (d, 6H). LC-MS (El), m/z: 208 (M+1). Preparedfrom N-Boc-Leucine.

[0233] (S,S)1-[2-Amino-3-(4-methoxy-phenyl)-propionyl]-2,5-dihydro-1H-pyrrole-2-carbonitrile(6) (61 mg) 1H-NMR (CDCl3, 200 MHz) δ: 7.15 (d, 2H); 6.76 (d, 2H); 5.85(d, 1H); 5.68 (d, 1H); 5.30 (s, 1H); 4.38 (m, 1H); 4.25 (d, 1H); 3.73(s, 3H); 3.32 (m, 1H); 3.12 (m, 2H). LC-MS (El), m/z: 272 (M+1).Prepared from (S)2-tert-Butoxycarbonylamino-3-(4-methoxy-phenyl)-propionic acid.

[0234] (2S)1-(2′-Amino-2′-phenyl-acetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile (7)

[0235] (68 mg) 1H-NMR (CDCl3, 200 MHz) δ: 7.48 (m, 5H); 5.57 (d, 1H);5.75 (d, 1H); 5.43 d, 1H); 5.37 (s, 1H); 4.50 (dd, 1H); 3.75 (dd, 1H).LC-MS(El), m/z: 228 (M+1). Prepared from (S)-Phenylglycine.

[0236] (S,S)1-(2-Amino-3-benzyloxy-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(8)

[0237] (61 mg) 1H-NMR (CDCl3, 200 MHz) δ: 7.32 (m, 5H); 6.05 (dd, 1H);5.82 (dd, 1H); 5.45 (dd, 1H); 4.68-4.42 (m, 4H); 4.15 (dd, 1H); 3.83 d,2H). LC-MS(El), m/z: 272 (M+1). Prepared from N-Boc-O-benzylserine.

[0238] (S,S)1-(2-Amino-4-methylsulfanyl-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(9)

[0239] (65 mg) 1H-NMR (CDCl3, 200 MHz) δ:6.15 (dd, 1H); 5.88 (dd, 1H);5.52 (m, 1H); 4.58 (dd, 2H); 4.40 (t, 1H); 2.65 (m, 2H); 2.22 (m, 2H);2.15 (s, 3H) LC-MS(El), m/z: 226 (M+1). Prepared from N-Boc-methionine.

[0240] (S,S)1-(2-Amino-2-cyclohexyl-acetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(10)

[0241] (116 mg) 1H-NMR (CDCl3, 200 MHz) δ: 6.09 (d, 1H); 5.83 (d, 1H);5.55 (s, 1H); 4.62 (d, 1H); 4.35 (d, 1H); 4.07 (d, 1H); 1.80 (m, 6H);1.2 (m, 5H). LC-MS(El), m/z: 234 (M+1). Prepared from (S)N-Boc-cyclohexylglycine

[0242] (2S,2′S,3′R)1-(2′-Amino-3′-methyl-pentanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(11 )

[0243] (46 mg)1H-NMR (CDCl3, 200 MHz) δ: 6.15 d(1 H); 5.38 (d, 1H); 5.53(s, 1H); 4.62 (d, 1H); 4.35 (d, 1H); 4.19 (d, 1H)1.96 (m, 1H); 1,60 (m,1H); 1.38 (m, 1H); 1.1 (m, 6H). LC-MS(El), m/z: 208 (M+1). Prepared fromN-Boc-allo-isoleucine

[0244] (2S)1-(2′-Amino-2′-naphthalen-1-yl-acetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(12)

[0245] (8 mg) 1H-NMR (CDCl3, 200 MHz) δ: 8.30 (d, 1H); 7.95 (t, 2H);7.60 (m, 4H); 5.87 (m, 1H); 5.78 (m, 1H); 5.52 (m, ½H); 5.40 (m, %2H);4.43 (m, 1H); 4.45 (m, 1H); 4.38 (m, 1H); 3.40 (m, 1H) LC-MS(El), m/z:277 (M). Prepared from (S) N-Boc-2-naphtylglycine

[0246] (2S,2′S,3′S),1-(2′-Amino-3′-methyl-pentanoyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(13)

[0247] (41 mg) 1H-NMR (CDCl3, 200 MHz) δ: 6.12 (dd, 1H); 5.85 (dd, 1H);5.48 (dd, 1H); 4.62 (dd, 1H); 4.35 (m, 1H); 4.05 (d, 1H); 2.0 (m, 1H);1.61 (m, 1H); 1.27 (m, 1H); 1.07 (d, 3H); 0.97 (t, 3H). LC-MS(El), m/z:208 (M+1). Prepared from N-Boc-isoleucine

[0248] (S,S)1-[2-Amino-3-(4-fluoro-phenyl)-propionyl]-2,5-dihydro-1H-pyrrole-2-carbonitrile(14)

[0249] (51 mg) 1H-NMR (CDCl3, 200 MHz) δ: 7.25 (m, 2H); 7.15 (m, 2H);5.90 (m, 1H); 5.74 (m, 1H); 5.38 (m, 1H); 4.25 (m, 2H); 3.17 (m, 3H).LC-MS(El), m/z: 260 (M+1). Prepared from N-Boc-p-fluorophenylglycine.

[0250] 3-Amino-4-(2-cyano-2,5-dihydro-pyrrol-1-yl)-4-oxo-butyric acidmethyl ester (15)

[0251] (21 mg) LC-MS(ES), m/z: 224 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 6.23(m, 1H); 5.95 (m, 1H); 5.53 (m, 1H); 4.55 (m, 3H); 3.75 (s, 3H); 3.72(t, 1H); 3.18-2.79 (m, 3H).

[0252] (S,S) 1-(2-Amino-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(16)

[0253] (13 mg) LC-MS(ES), m/z: 166 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 6.25(m, 1H); 5.98 (m, 1H); 5.54 (m, 1H); 4.50 (m, 2H); 4.27 (q, 1H); 1.57(d, 3H).

[0254] 3-Amino-4-(2-cyano-2,5-dihydro-pyrrol-1-yl)-4-oxo-butyric acidbenzyl ester (17)

[0255] (33 mg) LC-MS(ES), m/z: 300 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 7.36(m, 5H); 6.19 (m, 1H); 5.95 (m, 1H); 5.52 (m, 1H); 5.20 (s, 2H);4.63-4.42 (m, 3H); 3.35-2.97 (m, 2H).

[0256] 4-Amino-5-(2-cyano-2,5-dihydro-pyrrol-1-yl)-5-oxo-pentanoic acidbenzyl ester (18)

[0257] (39 mg) LC-MS(ES), m/z: 314 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 7.35(m, 5H); 6.20 m, 1H); 5.95 (m, 1H); 5.53 (m, 1H); 5.18 (s, 2H); 4.45 (m,2H); 4.35 (dd, 1H); 2.63 (t, 2H); 2.23 (m, 2H).

[0258]1-(2-Amino-3,3-diphenyl-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(19)

[0259] (1 mg) LC-MS(ES), m/z: 318 (M+1)

[0260] (2S,2′R)1-(2-Amino-3-methyl-3-methylsulfanyl-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(20)

[0261] (49 mg) LC-MS(ES), m/z: 240 (M+1).

[0262] (S,S)1-(2-Amino-3-cyclohexyl-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(21)

[0263] (30 mg) LC-MS(ES), m/z: 248 (M+1).

[0264]1-[2-Amino-3-(1-benzyl-1H-imidazol-4-yl)-propionyl]-2,5-dihydro-1H-pyrrole-2-carbonitrile(22).

[0265] (6 mg) LC-MS(ES), m/z: 322 (M+1).

[0266] (S,S)1-(2-Amino-3-mercapto-3-methyl-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(23)

[0267] (23 mg) LC-MS(ES), m/z: 490 (M+Na⁺). 1H-NMR (MEOH, 200 MHz) δ:7.24 (m, 15H); 6.23 (m, 1H); 5.98 (m, 1H); 5.57 (m, 1H); 4.60 (m, 2H);4.30 (s, 1H); 1.58 (s, 3H); 1.52 (s, 3H).

[0268]1-[2-Amino-3-(4-methoxy-benzylsulfanyl)-3-methyl-butyryl]-2,5-dihydro-1H-pyrrole-2-carbonitrile(25)

[0269] (3 mg) LC-MS(ES), m/z: 346 (M+1).

[0270] (S,S)1-[2-Amino-3-methyl-3-(4-methyl-benzylsulfanyl)-butyryl]-2,5-dihydro-1H-pyrrole-2-carbonitrile(26)

[0271] (58 mg) LC-MS(ES), m/z: 330 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 7.32(d, 2H); 7.13 (d, 2H); 6.20 (m, 1H); 5.95 (m, 1H); 5.52 (m, 1H); 4.42(m, 2H); 4.07 (s, 1H); 3.90 (dd, 2H); 2.30 (s, 3H); 1.58 (s, 3H); 1.46(s, 3H).

[0272]1-[2-Amino-2-(4-fluoro-phenyl)-acetyl]-2,5-dihydro-1H-pyrrole-2-carbonitrile(27)

[0273] (56 mg) LC-MS(ES), m/z: 246 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 7.50(m, 2H); 7.29 (m, 2H); 6.12 (m, 1H); 5.92, (m, 1H); 5.58 (m, 1H); 5.40(s, 1H); 4.50 (dd, 1H); 3.75 (m, 1H).

[0274] (S,S)1-(2-Amino-2-indan-4-yl-acetyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(28)

[0275] (65 mg) LC-MS(ES), m/z: 268 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 7.20(m, 3H); 6.23 (m, 1H); 5.97 (m, 1H); 5.56 (m, 1 H); 4.53 (m, 2H); 4.48(s, 1H); 3.20-2.96 (m, 6H).

[0276] (S,S)1-(2-Amino-3-methyl-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile (29)

[0277] (42 mg) LC-MS(ES), m/z: 195 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 6.05(m, 1H); 5.89 (m, 1H); 5.21 (m, 1H); 4.52-4.38 (m, 2H); 4.15-4.00 (m,1H); 2.50-2.15 (m, 1H); 1.18 d, 3H); 1.08 (d, 3H).

[0278]1-(5,5-Dimethyl-thiazolidine-4-carbonyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(30)

[0279] (115 mg) LC-MS(ES), mlz: 238 (M+1),

[0280] 1(1-Amino-cyclopropanecarbonyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile (31)

[0281] (45 mg) LC-MS(ES), m/z: 178 (M+1)

[0282] (S,S)1-(2-Amino-3-phenyl-propionyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(32)

[0283] (57 mg) LC-MS(ES), m/z: 242 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 7.34(s, 5H); 5.95 (m, 1H); 5.83 (m, 1H); 5.45 (m, 1H); 4.45 (m, 1H); 4.25(m, 1H); 3.33-3.00 (m, 3H).

[0284] 1-(2-Amino-butyryl)-2,5-dihydro-1H-pyrrole-2-carbonitrile (33)

[0285] (60 mg) LC-MS(ES), m/z: 180 (M+1). 1H-NMR (MEOH, 200 MHz) δ: 6.25(m, 1H); 5.96 (m, 1H); 5.55 (m, 1H); 4.50 (m, 2H); 4.22 (t, 1H); 2.00(m, 2H); 1.18 (t, 3H).

[0286]1-[2-Amino-3-(1H-indol-3-yl)-propionyl1-2,5-dihydro-1H-pyrrole-2-carbonitrile(34)

[0287] (53 mg) LC-MS(ES), m/z: 281 (M+1). 1H-NMR (MEOH, 200 MHz) δ:7.70-7.03 (m, 5H); 5.90 (m, 1H); 5.80 (m, 1H); 5.45 (m, 1H); 4.42 (m,1H); 4.20 (m, 1H); 3.45-3.15 (m, 3H).

[0288] (S,S)1-(Piperidine-2-carbonyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile (35)

[0289] (177 mg) 1H-NMR (MEOH, 300 MHz) δ: 6.25 (m, 1H); 5.98 (m, 1 H);5.53 (m, 1H); 4.49 (m, 2H); 4.15 (m, 1H); 3.43 (m, 1H); 3.08 (m, 1H);2.29 (m, 1H); 1.95 (m, 2H); 1.71 (m, 3H).

[0290] (S,S)1-(1,2,3,4-Tetrahydro-isoquinoline-3-carbonyl)-2,5-dihydro-1H-pyrrole-2-carbonitrile(36)

[0291] (357 mg). 1H-NMR (MEOH, 300 MHz) δ: 7.30 (m, 4H); 6.28 (m, 1H);6.01 (m, 1H); 5.60 (m, 1H); 4.63-4.42 (m, 5H); 3.52 (dd, 1H); 3.19 (dd,1H).

[0292]1-(2-Amino-cyclopentanecarbonyl)-2,5-dihydro-1H-pyrrole-2-S-carbonitrile(37)

[0293] LC-MS(ES), m/z: 206 (M+1).

[0294] 1-(Piperidine-3-carbonyl)-2,5-dihydro-1H-pyrrole-2-S-carbonitrile(38)

[0295] LC-MS(ES), m/z: 206 (M+1).

[0296]1-((3R)-Amino-5-phenyl-pentanoyl)-2,5-dihydro-1H-pyrrole-(2S)-carbonitrile(39)

[0297] LC-MS(ES), m/z: 270 (M+1).

[0298]1-((3S)-Amino-4-phenyl-butyryl)-2,5-dihydro-1H-pyrrole-(2S)-carbonitrile(40)

[0299] LC-MS(ES), m/z: 256 (M+1).

[0300] 1-(Morpholine-2-carbonyl)-2,5-dihydro-1H-pyrrole-2-S-carbonitrile(41)

[0301] LC-MS(ES), m/z: 208 (M+1).

[0302]1-(3-Amino-6-phenyl-hex-5-enoyl)-2,5-dihydro-1H-pyrrole-2-S-carbonitrile(42)

[0303] LC-MS(ES), m/z: 281 (M+1).

[0304]1-[(3S)-Amino-4-(4-benzyloxy-phenyl)-butyryl]-2,5-dihydro-1H-pyrrole-(2S)-carbonitrile(43)

[0305] LC-MS(ES), m/z: 361 (M+1).

[0306]1-(2-Pyrrolidin-2-yl-acetyl)-2,5-dihydro-1H-pyrrole-2-S-carbonitrile(44)

[0307] LC-MS(ES), m/z: 206 (M+1).

[0308]1-[4-(2-Chloro-phenyl)-pyrrolidine-3-carbonyl]-2,5-dihydro-1H-pyrrole-2-S-carbonitrile(45)

[0309] LC-MS(ES), m/z: 302 (M+1).

[0310]1-(4-Phenyl-pyrrolidine-3-carbonyl)-2,5-dihydro-1H-pyrrole-2-S-carbonitrile(46)

[0311] LC-MS(ES), m/z: 268 (M+1).

Example 2

[0312]1-[2-(R,S)-(4-Cyanophenyl)thiazolidine-4-(R)-carbonyl]-2,5-dihydro-1H-pyrrole-2-(S)-carbonitrile(47)

[0313] 4-Cyanobenzaldehyde (500 mg, 3.8 mmol) was dissolved in 5 ml ofethanol (96%) and L-(+)-cysteine hydrochloride (460 mg, 3.8 mmol) andnatriumacetate trihydrate (468 mg, 5.7 mmol) dissolved in 5 ml of waterwas added. The reaction mixture was stirred for 16 hours at roomtemperature and the white crystals were collected by filtration andwashed twice with 15 ml of water:ethanol (1:1), to afford 400 mg of2-(RS)-(4-cyanophenyl)thiazolidine-4-(R)-carboxylic acid (48) in 44%yield. 1H-NMR (MEOH, 300 MHz) δ: 7.69 (m, 4H); 5.81 (s, ½H); 5.60 (s,½H); 4.23 (dd, ½H); 4.02 (dd, ½H); 3.52-3.17 (m, 2H).

[0314] (265 mg, 1.13 mmol) of (48) was dissolved in 10 ml oftetrahydrofuran, 5 ml of water, and (0.452 ml, 1.13 mmol) of a 10%aqueous solution of sodium hydroxide. Di-tert.-butyl dicarbonate (321mg, 1.47 mmol) was added and the reaction mixture was stirred for 5days. Tetrahydrofuran was evaporated off and the remaining was dissolvedin 50 ml of ethyl acetate and 50 ml of water, and solid potassiumhydrogen sulphate was added until pH=2. The organic material wasextracted into 4×50 ml of ethyl acetate and the combined organicextracts were washed with 100 ml of water, and 100 ml of brine, anddried over sodium sulphate. The solvent was evaporated to afford 340 mgof 2-(RS)-(4-cyanophenyl)thiazolidine-4-(R)-carboxylic acid 3-carboxylicacid tert-butyl ester (49) as beige crystals in 90% yield. 1H-NMR(CDCl3, 300 MHz) δ: 7.62 (m, 4H); 6.21-5.41 (m, 1H); 5.02-4.78 (m, 1H);3.47-3.21 (m, 2H); 1.42 (s, 3H); 1.24 (s, 6H). LC-MS(ES), m/z: 235.1(M-99(BOC) and 357.2 (M+23(Na)).

[0315] (49) was coupled to (S) 2,5-dihydro-1H-pyrrole-2-carboxylic acidamide and dehydrated with phosphorus oxychloride and finally deprotectedwith trifluoroacetic acid as described in example 1, and purified bypreparative HPLC to afford 52 mg of the title compound (47). 1H-NMR(MEOH, 300 MHz) δ: 7.75-7.63 (m, 4H); 6.24 (m, 1 H); 5.95 (m, 1H); 5.82(s, ½H); 5.65 (s, ½H); 5.48 (m, 1 H); 4.69 (m, 1 H); 4.49 (m, 1H); 4.27(m, 1H); 3.48 (m, 1H); 3.22 (m, 1H). LC-MS(ES), m/z: 311.2 (M+1)

[0316] The following compounds were prepared by the route outlined inexample 2; however, all compounds were also purified by preparative HPLCafter the dehydration step.

[0317]1-[2-(R,S)-(1-(R,S)-Phenylethyl)thiazolidine-4-(R)-carbonyl]-2,5-dihydro-1H-pyrrole-2-(S)-carbonitrile(50)

[0318] (32 mg) 1H-NMR (MEOH, 300 MHz) δ:) δ: 7.41-7.15 (m, 5H); 6.80(dd, ½H); 6.45 (dd, ½H); 6.20 (m, 1H); 5.92 (m, 1H); 5.70 (d, ½H); 5.51(d, ½H); 5.45 (m, 1H); 4.68-4.29 (m, 2H); 4.12-3.88 (m, 1H); 3.81-2.82(m, 3H); 1.40 (m, 3H). LC-MS(ES), m/z: 314.2 (M+1).

[0319]1-(2-(R,S)-Phenylthiazolidine-4-(R)-carbonyl)-2,5-dihydro-1H-pyrrole-2-(S)-carbonitrile(51)

[0320] (40 mg) 1H-NMR (MEOH, 300 MHz) δ:) δ: 7.40 (m, 5H); 6.73 (m, ½H);6.48 (m, ½H); 6.25 (m, 1H); 5.98 (m, 1H); 5.52 (m, 1H); 5.11 (m, 1H);4.72-3.91 (m, 3H); 3.69-2.91 (m, 2H). LC-MS(ES), m/z: 286.2 (M+1).

[0321]1-(Thiazolidine-4-(R)-carbonyl)-2,5-dihydro-1H-pyrrole-2-(S)-carbonitrile(52)

[0322] (R)-(−)-Thiazolidine-4-carboxylic acid was used as the startingmaterial instead of L-(+)-cysteine hydrochloride as in example 2. Thetitle compound was synthesised as outlined in example 2, starting at theBOC-protection step, to afford 46 mg of (X+7). LC-MS(ES), m/z: 210(M+1).

What is claimed is:
 1. A compound of formula I

wherein at least one of the bonds in the five-membered ring is a doublebond; B is any alpha or beta amino acid connected to the ring with anamide or peptide bond; or a salt thereof with a pharmaceuticallyacceptable acid or base.
 2. A compound of formula II

wherein at least one of the bonds in the five-membered ring is a doublebond; R² is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently; R³ is H; C₁-C₁₀ alkyl optionally substituted with one ormore R⁴ independently; C₂-C₁₀ alkenyl optionally substituted with one ormore R⁴ independently; C₂-C₁₀-alkynyl optionally substituted with one ormore R⁴ independently; C₃-C₁₀ cycloalkyl optionally substituted with oneor more R⁴ independently; C₅-C₁₀ cycloalkenyl optionally substitutedwith one or more R⁴ independently; aryl optionally substituted with oneor more R⁵ independently and/or fused to a C₃-C₁₀ cycloalkane; orheteroaryl optionally substituted with one or more R⁵ independentlyand/or fused to a C₃-C₁₀ cycloalkane; R² may be connected to R³ by asaturated or unsaturated bridge containing 1-3 carbon atoms, nitrogenatoms, oxygen atoms or sulphur atoms independently, or a valence bond,thus forming a ring, said ring may be fused to an aryl or heteroaryl,optionally substituted by one or more R⁵ independently; R⁴ iscycloalkyl, aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; amino optionally substituted with one or more R⁶independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶, —CONH—R⁶; —CON(R⁶)₂;—O—R⁶; —S—R⁶; carboxy; acetamido; cyano; nitro; halogen; hydroxy;trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano; carboxy;acetamido; hydroxy; sulfamoyl, carbamoyl; R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀-alkynyl, C₃-C₁₀-cycloalkyl, C₅-C₁₀ cycloalkenyl whereany one of said alkyl, alkenyl, alkynyl, cycloalkyl, or cykloalkenyl mayoptionally be substituted with aryl optionally substituted with one ormore R⁵ independently or heteroaryl optionally substituted with one ormore R⁵ independently; benzyl, phenethyl; aryl optionally substitutedwith one or more R⁵ independently; or heteroaryl optionally substitutedwith one or more R⁵ independently with the proviso that R² and R³ cannotboth be H; or a salt thereof with a pharmaceutically acceptable acid orbase.
 3. A compound of formula III

wherein R² is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently; R³ is H; C₁-C₁₀ alkyl optionally substituted with one ormore R⁴ independently; C₂-C₁₀ alkenyl optionally substituted with one ormore R⁴ independently; C₂-C₁₀-alkynyl optionally substituted with one ormore R⁴ independently; C₃-C₁₀ cycloalkyl optionally substituted with oneor more R⁴ independently; C₅-C₁₀ cycloalkenyl optionally substitutedwith one or more R⁴ independently; aryl optionally substituted with oneor more R⁵ independently and/or fused to a C₃-C₁₀ cycloalkane; orheteroaryl optionally substituted with one or more R⁵ independentlyand/or fused to a C₃-C₁₀ cycloalkane; R² may be connected to R³ by asaturated or unsaturated bridge containing 1-3 carbon atoms, nitrogenatoms, oxygen atoms or sulphur atoms independently, or a valence bond,thus forming a ring, said ring may be fused to an aryl or heteroaryl,optionally substituted by one or more R⁵ independently; R⁴ iscycloalkyl, aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; amino optionally substituted with one or more R⁶independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶, —CONH—R⁶; —CON(R⁶)₂;—O—R⁶; —S—R⁶; carboxy; acetamido; cyano; nitro; halogen; hydroxy;trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano; carboxy;acetamido; hydroxy; sulfamoyl, carbamoyl; R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀-alkynyl, C₃-C₁₀-cycloalkyl, C₅-C₁₀ cycloalkenyl whereany one of said alkyl, alkenyl, alkynyl, cycloalkyl, or cykloalkenyl mayoptionally be substituted with aryl optionally substituted with one ormore R⁵ independently or heteroaryl optionally substituted with one ormore R⁵ independently; benzyl, phenethyl; aryl optionally substitutedwith one or more R⁵ independently; or heteroaryl optionally substitutedwith one or more R⁵ independently with the proviso that R² and R³ cannotboth be H; or a salt thereof with a pharmaceutically acceptable acid orbase.
 4. A compound of formula IV

wherein at least one of the bonds in the five-membered ring is a doublebond; R² is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently; R³ is H; C₁-C₁₀ alkyl optionally substituted with one ormore R⁴ independently; C₂-C₁₀ alkenyl optionally substituted with one ormore R⁴ independently; C₂-C₁₀-alkynyl optionally substituted with one ormore R⁴ independently; C₃-C₁₀ cycloalkyl optionally substituted with oneor more R⁴ independently; C₅-C₁₀ cycloalkenyl optionally substitutedwith one or more R⁴ independently; aryl optionally substituted with oneor more R⁵ independently and/or fused to a C₃-C₁₀ cycloalkane; orheteroaryl optionally substituted with one or more R⁵ independentlyand/or fused to a C₃-C₁₀ cycloalkane; R² may be connected to R³ or R⁷ bya saturated or unsaturated bridge containing 1-3 carbon atoms, nitrogenatoms, oxygen atoms or sulphur atoms independently, or a valence bond,thus forming a ring, said ring may be fused to an aryl or heteroaryl,optionally substituted by one or more R⁵ independently; R⁴ iscycloalkyl, aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; amino optionally substituted with one or more R⁶independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶, —CONH—R⁶; —CON(R⁶)₂;—O—R⁶; —S—R⁶; carboxy; acetamido; cyano; nitro; halogen; hydroxy;trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano; carboxy;acetamido; hydroxy; sulfamoyl, carbamoyl; R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀-alkynyl, C₃-C₁₀-cycloalkyl, C₅-C₁₀ cycloalkenyl whereany one of said alkyl, alkenyl, alkynyl, cycloalkyl, or cykloalkenyl mayoptionally be substituted with aryl optionally substituted with one ormore R⁵ independently or heteroaryl optionally substituted with one ormore R⁵ independently; benzyl, phenethyl; aryl optionally substitutedwith one or more R⁵ independently; or heteroaryl optionally substitutedwith one or more R⁵ independently; R⁷ is H; C₁-C₁₀ alkyl optionallysubstituted with one or more R⁴ independently; C₂-C₁₀ alkenyl optionallysubstituted with one or more R⁴ independently; C₂-C₁₀-alkynyl optionallysubstituted with one or more R⁴ independently; C₃-C₁₀-cycloalkyloptionally substituted with one or more R⁴ independently; C₅-C₁₀cycloalkenyl optionally substituted with one or more R⁴ independently;aryl optionally substituted with one or more R⁵ independently;heteroaryl optionally substituted with one or more R⁵ independently,halogen, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, N-hydroxyimino, cyano; carboxy; acetamido; hydroxy;sulfamoyl, carbamoyl; with the proviso that the groups R², R³, and R⁷cannot all be H. or a salt thereof with a pharmaceutically acceptableacid or base.
 5. A compound of formula V

wherein R² is H; C₁-C₁₀ alkyl optionally substituted with one or more R⁴independently; C₂-C₁₀ alkenyl optionally substituted with one or more R⁴independently; C₂-C₁₀-alkynyl optionally substituted with one or more R⁴independently; C₃-C₁₀-cycloalkyl optionally substituted with one or moreR⁴ independently; C₅-C₁₀ cycloalkenyl optionally substituted with one ormore R⁴ independently; aryl optionally substituted with one or more R⁵independently; or heteroaryl optionally substituted with one or more R⁵independently; R³ is H; C₁-C₁₀ alkyl optionally substituted with one ormore R⁴ independently; C₂-C₁₀ alkenyl optionally substituted with one ormore R⁴ independently; C₂-C₁₀-alkynyl optionally substituted with one ormore R⁴ independently; C₃-C₁₀ cycloalkyl optionally substituted with oneor more R⁴ independently; C₅-C₁₀ cycloalkenyl optionally substitutedwith one or more R⁴ independently; aryl optionally substituted with oneor more R⁵ independently and/or fused to a C₃-C₁₀ cycloalkane; orheteroaryl optionally substituted with one or more R⁵ independentlyand/or fused to a C₃-C₁₀ cycloalkane; R² may be connected to R³ or R⁷ bya saturated or unsaturated bridge containing 1-3 carbon atoms, nitrogenatoms, oxygen atoms or sulphur atoms independently, or a valence bond,thus forming a ring, said ring may be fused to an aryl or heteroaryl,optionally substituted by one or more R⁵ independently; R⁴ iscycloalkyl, aryl optionally substituted with one or more R⁵independently; heteroaryl optionally substituted with one or more R⁵independently; amino optionally substituted with one or more R⁶independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶, —CONH—R⁶; —CON(R⁶)₂;—O—R⁶; —S—R⁶; carboxy; acetamido; cyano; nitro; halogen; hydroxy;trifluoromethyl; trifluoromethoxy; sulfamoyl; carbamoyl; hydroxymethyl;R⁵ is halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, benzyl, benzyloxy, hydroxymethyl, nitro, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, N-hydroxyimino, cyano; carboxy;acetamido; hydroxy; sulfamoyl, carbamoyl; R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, C₂-C₁₀-alkynyl, C₃-C₁₀-cycloalkyl, C₅-C₁₀ cycloalkenyl whereany one of said alkyl, alkenyl, alkynyl, cycloalkyl, or cykloalkenyl mayoptionally be substituted with aryl optionally substituted with one ormore R⁵ independently or heteroaryl optionally substituted with one ormore R⁵ independently; benzyl, phenethyl; aryl optionally substitutedwith one or more R⁵ independently; or heteroaryl optionally substitutedwith one or more R⁵ independently; R⁷ is H; C₁-C₁₀ alkyl optionallysubstituted with one or more R⁴ independently; C₂-C₁₀ alkenyl optionallysubstituted with one or more R⁴ independently; C₂-C₁₀-alkynyl optionallysubstituted with one or more R⁴ independently; C₃-C₁₀-cycloalkyloptionally substituted with one or more R⁴ independently; C₅-C₁₀cycloalkenyl optionally substituted with one or more R⁴ independently;aryl optionally substituted with one or more R⁵ independently;heteroaryl optionally substituted with one or more R⁵ independently,halogen, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, N-hydroxyimino, cyano; carboxy; acetamido; hydroxy;sulfamoyl, carbamoyl; with the proviso that the groups R², R³, and R⁷cannot all be H; or a salt thereof with a pharmaceutically acceptableacid or base.
 6. A compound of claim 2 , wherein R² is H; C₁-C₁₀ alkyloptionally substituted with R⁴; C₂-C₁₀ alkenyl optionally substitutedwith R⁴; C₂-C₁₀-alkynyl optionally substituted with R⁴; aryl optionallysubstituted with one or more R⁵ independently; or heteroaryl optionallysubstituted with one or more R⁵ independently; or R² is connected to R³or R⁷ by a saturated or unsaturated bridge containing 1-3 carbon atoms,nitrogen atoms, oxygen atoms, or sulphur atoms independently, or avalence bond, thus forming a ring, said ring may be fused to an aryl orheteroaryl, optionally substituted by one or more R⁵ independently;
 7. Acompound of claim 6 , wherein R² is H or C₁-C₁₀ alkyl optionallysubstituted with R⁴.
 8. A compound of claim 7 , wherein R² is H.
 9. Acompound of claim 2 , wherein R³ is H; C₁-C₁₀ alkyl optionallysubstituted with R⁴; C₂-C₁₀ alkenyl optionally substituted with R⁴;C₂-C₁₀-alkynyl optionally substituted with R⁴; C₃-C₁₀ cycloalkyloptionally substituted with R⁴; aryl optionally substituted with one ormore R⁵ independently and/or fused to a C₃-C₁₀ cycloalkane; orheteroaryl optionally substituted with one or more R⁵ independentlyand/or fused to a C₃-C₁₀ cycloalkane;
 10. A compound of claim 9 ,wherein R³ is H; C₁-C₁₀ alkyl optionally substituted with R⁴; or aryloptionally substituted with one or more R⁵ independently and/or fused toa C₃-C₁₀ cycloalkane.
 11. A compound of claim 10 , wherein R³ is C₁-C₁₀alkyl optionally substituted with R⁴.
 12. A compound of claim 2 ,wherein R⁴ is cycloalkyl; aryl optionally substituted with one or moreR⁵ independently; heteroaryl optionally substituted with one or more R⁵independently; —SO—R⁶; —SO₂—R⁶; —CO—R⁶; —COO—R⁶; —O—R⁶; or —S—R⁶.
 13. Acompound of claim 12 , wherein R⁴ is aryl optionally substituted withone or more R⁵ independently; heteroaryl optionally substituted with oneor more R⁵ independently; —CO—R⁶; —COO—R⁶; —O—R⁶; or —S—R⁶.
 14. Acompound of claim 13 , wherein R⁴ is aryl optionally substituted withone or more R⁵ independently.
 15. A compound of claim 13 , wherein R⁴ is—COO—R⁶, —O—R⁶, or —S—R⁶.
 16. A compound of claim 2 , wherein R⁵ ishalogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylamino, C₁-C₁₀dialkylamino, benzyl, or benzyloxy.
 17. A compound of claim 16 , whereinR⁵ is halogen, C₁-C₁₀ alkyl, or C₁-C₁₀ alkoxy.
 18. A compound of claim 2, wherein R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl optionally substituted withR⁴; C₂-C₁₀-alkynyl optionally substituted with R⁴; benzyl, aryloptionally substituted with one or more R⁵ independently, or heteroaryloptionally substituted with one or more R⁵ independently.
 19. A compoundof claim 18 , wherein R⁶ is C₁-C₁₀ alkyl, benzyl, or aryl optionallysubstituted with one or more R⁵ independently.
 20. A pharmaceuticalcomposition comprising, as an active ingredient, at least one compoundof claim 1 or a pharmaceutically acceptable salt or prodrug or hydratethereof together with a pharmaceutically acceptable carrier or diluent.22. A method of treating type II diabetes in a human, which methodcomprises administering to the human an effective amount of a compoundof claim 1 .